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Thalassemia

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What is Thalassemia and how to approach

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Thalassemia

  1. 1. WELCOME TO SEMINAR Dr. Aysha Sabiha Dr. Maimuna Sayeed Dr. Sharmin Akter Luna Residents (Phase-A)
  2. 2.  Halima, a 11 years old girl of consanguineous parents presented with complaints of not growing well, gradual pallor & abdominal distension for 7 years.  On examination she was severely pale, facial dysmorphism & hepatosplenomegaly were present. She had history of repeated blood transfusion. Case Scinerio
  3. 3. Hereditary hemolytic anemia Diagnosis
  4. 4. SEMINAR ON THALASSEMIA
  5. 5. Introduction The term “Thalassemia” refers to a genetic disorder of hemoglobin synthesis characterized by a lack or decreased synthesis of one or more of the four Globin chains causing excessive breakdown of RBC. "Thalassemia" is a Greek term derived from “Thalassa”, which means "the sea" and “Emia” means "related to blood."
  6. 6. World: • Beta thalassemia trait - 8% of population • More than - 100 million carrier • Hb E - 53 millions Bangladesh: • Beta thalassemia trait- 4.1% • Hb E trait - 6.1% • Hb E Beta thalassemia- 10.2% (Source: DSH Thalassemia center) Incidence
  7. 7. Site of synthesis of globin
  8. 8. Normal hemoglobin component Hb type Name Components Adult A α2β2 A2 α2δ2 Fetal F α2γ2 Embryonic Portland ξ2γ2 Gower 1 ξ2ε2 Gower 2 α2ε2
  9. 9.     HbA 98% HbA2 <3.5% HbF ~1%         Hemoglobin in normal adult
  10. 10. • α Thalassemia • β Thalassemia Types of thalassemia
  11. 11. Autosomal recessive Inheritance
  12. 12. α-THALASSEMIA
  13. 13. Chromosome 16 defect 2 1 2 1 2 2 1 2 1 2 1 2 1 2 1 2 1 Normal Hb One α gene deletion silent carrier Two α gene deletions- α-Thal. Minor Four α gene deletions Hydrops fetalis or also called: Erythroblastosis Fetalis. Three α gene deletions Hb-H disease
  14. 14. CLINICAL PRESENTATION Variants of alpha thalassemia Signs &Symptoms Silent carrier Asymptomatic Trait Asymptomatic Hb H disease Moderate to severe hemolytic anemia Modest degree of ineffective erythropoiesis Splenomegaly Variable bone changes Hb Bart's Born with massive generalized edema, usually fatal
  15. 15. Diagnosis of α-Thalassemia CBC: • Silent Carrier: no microcytosis , no anaemia. • α-Thalassemia trait: microcytosis, hypochromia, mild anaemia. • Hb H disease: variable severity of anaemia & hemolysis. PBF: Hb H inclusion body (brilliant cresyl blue) in Hb H disease.
  16. 16. Hb electrophoresis – Hb H: • (2-40%) Hb H • others Hb A • Hb F & Hb A2 Hb Bart's: • (80-90%) Bart's, • no Hb A, Hb F, Hb A2 Diagnosis of α-thalassemia
  17. 17. Treatment of α-thalassemia • Silent carrier & trait: do not require treatment. • Hb H disease: usually does not require regular transfusions. But, with intercurrent illnesses, patient may require transfusion .
  18. 18. β-Thalassemia
  19. 19. With a mutation on one of the 2 beta globin genes , a carrier is formed with lower protein production but enough hemoglobin Without a mutation enough hemoglobin No carrier With one mutation less hemoglobin Beta thalassemia carrier but less hemoglobin Slight anemia With two mutation No beta globin Beta thalassemia major pt with severe anemia Gene from father Gene from mother Chromosome 11 gene defects
  20. 20. Clinical syndrome Genotype Sign & symptom Minor /  + or / ° Asymptomatic Intermedia  + / + Variable degree of severity Major  + /° or °/° - Present within 1 year of age - Severe anemia - Growth retardation - Organomegaly - Skeletal deformities -Transfusion require within 2 year Variants of β-thalassemia
  21. 21. An absence or deficiency of β- chain synthesis of adult HbAg Pathophysiology of β-thalassemia β Chain synthesis Hb-A α , γ and δ chain Hb A = α2β2
  22. 22. Pathophysiology of β-thalassemia
  23. 23. An approach to thalassemia • Severe Anemia • Thalassemic facies • Hepatosplenomegaly • Growth retardation, etc • Symptoms of anemia • +ve family history • H/0 blood transfusion • FTT
  24. 24. Thalassemia Major Child with no transfusion or inadequate transfusion Child with regular blood transfusion but no chelation Child with regular blood transfusion & chelation Leads natural course of disease, may die within 5 yrs of age Manifestation of iron overload at the end of 1st decade May enter into normal puberty & have normal life expectancy Clinical features
  25. 25. Natural course General features Weakness Gradual Pallor Fatigue Dyspnoea on exertion Poor appetite Palpitation Poor growth Features of marrow expansion
  26. 26. Features of extramedullary hematopoiesis Features of hemolysis Jaundice Hyperurecemia-Gout Gallstone Scoliosis,Kyphosis,vertebral collapse with cord compression
  27. 27. Features of iron overload Cirrhosis Diabetes Infertility Pituitary failure Hypothyroidism Arrythmia Heart failure Dark skin Liver Heart Endocrine organs
  28. 28. Hb E β-Thalassemia • Most prevalent thalassemia variant in Southeast Asia & Bangladesh. • Double heterozygous state. • Lysine substitutes glutamic acid in 26th position. • Divided into mild, moderate & severe form with clinical features varying from thalassemia intermedia to thalassemia major
  29. 29. Types Sign & symptom Mild Hb E β Thalassemia Asymptomatic , Hb :9 -12 gm/ dl , require no treatment . Moderately severe Hb E β Thalassemia Majority of patient are in this group, Hb : 6 -7 gm/dl , resemble Thalassemia intermedia. Severe Hb E β - Thalassemia Clinical manifestation resemble Thalassemia major (severe anaemia, growth retardation, hepatosplenomegaly, skeletal deformities). Hb: 4-5 gm/dl , treated as thalassemia major. Variants of Hb E β-thalassemia
  30. 30. Complications of thalassemia A. Excessive erythropoiesis B. Iron overload C. Chronic hemolysis D. Hypercoagulable disease E. Infection F. Treatment of related complications
  31. 31. Facial changes: • Maxillary over growth • Malocclusion of teeth • Frontal bossing • Chronic sinusitis • Impaired hearing A. Excess erythropoiesis
  32. 32. • Medullary expansion – cortical thinning, risk of fracture, osteopenia, osteoporosis, back ache. • Vertebral expansion lead to spinal cord compression – neurological manifestations. Bone Changes
  33. 33. • Hepatosplenomegaly • Lymphadenopathy
  34. 34. Endocrine failure: • Short stature • Delayed puberty • Estrogen/ testosterone deficiency • Diabetes mellitus • Hypoparathyroidism B. Iron Overload
  35. 35. B. Iron overload Cardiac involvement: • Cardiomyopathy • Pericarditis • Arrhythmia • CCF
  36. 36. Hepatic involvement: Cirrhosis Hepatic fibrosis B. Iron overload
  37. 37. C. Chronic hemolysis • Gallstone 50-70% by around 15 years.
  38. 38. D. Hypercoagulable disease Impaired platelet function Deep venous thrombosis Elevated endothelial adhesion protein level Pulmonary embolism Activation of coagulation cascade by damage RBC Cerebral ischemia
  39. 39. E. Infection • Anemia • Iron overload – Yersinia, Klebsiella • Hypersplenism • Splenectomy – Pneumococci, Meningococci, Hemophilus influenzae • Transfusion related – HBV, HCV, HIV etc.
  40. 40. F. Complications due to blood transfusion • Acute hemolytic reactions • Delayed transfusion reaction • Autoimmune hemolytic anemia • Febrile transfusion reaction • Allergic reaction • Transfusion related acute lung injury (TRALI) • Graft versus host disease (GVHD) • Volume overload • Transfusion of disease – HAV, HBV, HIV
  41. 41. Causes of death in thalassemia • Congestive heart failure • Arrhythmia • Sepsis due to increase susceptibility to infection • Multiple organ failure due to hemochromatosis
  42. 42. INVESTIGATIONS
  43. 43. Investigations CBC: • Hb level - Depends on severity – β-thalassemia minor: 10-13 gm/dl – β-thalassemia intermedia: 7-10 gm/dl – β-thalassemia major: 3-6 gm/dl • TC/DC– normal / increased / decreased • Platelet- normal / decreased • RBC Indices- MCV, MCH, MCHC are low • RDW- Normal or raised • Reticulocyte count- Increased(5-10%) PBF: Microcytic hypochromic cells with marked anisocytosis, poikilocytosis and other abnormal cells.
  44. 44. Abnormal RBCs in PBF 1. Target cell 2. Tear drop cell 3. Elliptocyte 4. Hypochromic 5. Microcyte
  45. 45. PBF: Normal
  46. 46. PBF: β-thalassemia major
  47. 47. PBF: β-thalassemia minor
  48. 48. Investigations • Osmotic fragility: Decrease • Iron Profile:  S. Iron & ferritin- Increased  TIBC- Decreased  High % saturation of transferrin • S. bilirubin (indirect): Increased
  49. 49. Hb electrophoresis Hb NORMAL MAJOR MINOR INTERMEDIATE Hb F <1% 90-98% 1-5 % Variable Hb A 97% Absent 90-95% Variable Hb A2 1-3% Variable 3.5-7% >3.5%
  50. 50. Normal Hb electrophoresis
  51. 51. Hb electrophoresis of homozygous β° thalassemia
  52. 52. • Widened diploic spaces • Hair-on-end appearance • Thinning of cortex X-ray Skull
  53. 53. • Rectangular appearance • Medullary portion of bone is widened • Bony cortex thinned out • Coarse trabecular pattern in medulla X-ray of hand
  54. 54. Investigations • DNA analysis: Determine specific defect at molecular DNA level. • HPLC (High Performance Liquid Chromatography): Identify & quantify large number of abnormal Hb.
  55. 55. Normal 10% (33) β thalassemia trait 44% (145) homozygous β thalassemia 5% (18) Hb E β Thalassemia 16% (52) Hb E talassemia trait 21% (71) Hb E disease 2% (5) β-Thalassemia major 2% (7) Unknown 0% (1) Patient diagnose as different variety of thalassemia by DNA analysis in BSMMU during the period of Sept 2007 to Aug 2016 (Total=332)
  56. 56. Diagnosing Thalassemia Full medical and family history, CBC and RBC indices and PBF Low MCV (< 80fl) ± Low MCH (< 27pg) Other cause of anemia? Serum ferritin ≤12 ng/ml Consider iron deficiency anemia Adequate iron supplement for 3 months Hb electrophoresis and HPLC Improved Not improved Hb A2 variable Hb F > 90-98% Hb A2 ≥ 4% Hb F ≤ 0.1-5% Hb A2 > 4% Hb F variable Hb A2 < 4% Hb F < 1% + Other normal Hb variant ß-Thalassemia major ß-Thalassemia minor ß-Thalassemia intermedia 𝛼-Thalassemia Hb S, Hb E, Hb C and others DNA analysis for 𝛼-globin ß-globin chain mutation Serum ferritin >12 ng/ml Microcytosis, Hypochromia, Target cells ± inclusion bodies (Hb H)
  57. 57. To see complications • Liver function test • Thyroid function test • FSH, LH, Testosterone, Estradiol • Blood Sugar • Bone profile • Ca, Phosphate, PTH • Liver Iron Concentration (LIC): T2 MRI, Liver Biopsy • Cardiac Iron Measurement by: T2 MRI
  58. 58. • Bright areas represent high iron concentration. • Dark areas represent low iron concentration. Monitoring iron overload by MRI
  59. 59. MANAGEMENT OF THALASSEMIA
  60. 60. Treatment modalities A. Supportive B. Curative C. Preventive
  61. 61. A. Supportive management • Multi-disciplinary approach • Focus on each patient’s clinical course Transfusion Iron Chelation Fetal Hb Induction Splenectomy
  62. 62. Objectives of supportive management • Maintenance of growth and development • Correction of anemia • Prevention of iron overload • Treatment of complications • Counseling and Prevention
  63. 63. Blood Transfusion
  64. 64. Whom to transfuse? Confirmed diagnosis of thalassemia major • Laboratory criteria: • Hb < 7gm/dl on 2 occasions > 2 weeks apart or • Hb > 7gm/dl with: • Facial changes • Poor growth • Fractures • Extramedullary hematopoiesis
  65. 65. Important issues before starting transfusion • Blood grouping: – ABO and Rh(D) compatibility checked – Extended red cell antigen typing at least C, c, E, e and Kell. • Screening of donor blood for HBV, HCV, HIV, Syphilis, Malaria. • Avoidance of transfusion first-degree relative donors. • Quality, adequacy and safety of blood
  66. 66. Transfusion protocol To maintain pre transfusion Hb >9–9.5 gm/dl. • Typical programs: • Transfusion of 10–15 cc/kg of packed Leuko- depleted red cells • Lifelong regular blood transfusions, every 2–5 weeks
  67. 67. A higher pre-transfusion hemoglobin level of 11-12 gm/dl for patients with: • Heart disease or other medical conditions • Patients who do not achieve adequate suppression of bone marrow activity at lower Hb level.
  68. 68. Blood products for transfusion • Packed red cell • Leukocyte reduced red cell • Washed red cell • Neocyte
  69. 69. Target in  Hb Haematocrit of Donor Red Cells 50% 60% 75% 80% 1 gm/dl 4.2 ml/kg 3.5 ml/kg 2.8 ml/kg 2.6 ml/kg 2 gm/dl 8.4 ml/kg 7.0 ml/kg 5.6 ml/kg 5.2 ml/kg 3 gm/dl 12.6 ml/kg 10.5 ml/kg 8.4 ml/kg 7.8 ml/kg 4 gm/dl 16.8 ml/kg 14.0 ml/kg 11.2 ml/kg 10.4 ml/kg
  70. 70. Regularly Transfused Irregularly Transfused
  71. 71. • Normal growth • Normal physical activities • Adequately suppresses bone marrow activity • Minimizes iron accumulation Regular transfusion allows
  72. 72. Diet and supplementation • High iron contained food should be avoided. • Diet which decreases iron absorption such as milk & milk products should be taken adequately • Folic acid • Zinc • Vit. D, Vit. E
  73. 73. Thalassemic diet
  74. 74. CHELATION THERAPY
  75. 75. Chelator MetalChelator Toxic ExcretionMetal What is chelation therapy?
  76. 76. Evaluation of iron overload Serum ferritin concentration Liver iron concentration (LIC)  Liver biopsy – n=1.8 -7 mg/dry wt , >15-20 mg  SQUID  MRI Others: NTBI and T2*MRI Guideline- Thalassemia International Federation-2008
  77. 77. Guidelines for starting treatment of iron overload in patients with β-thalassemia major Thalassemia International Federation guidelines for the clinical management of thalassemia (2008)1 recommend that chelation therapy is considered when patients: Have received 10–20 transfusion episodes OR Have a serum ferritin level of >1000 ng/mL 1Thalassemia International Federation. Guidelines for the clinical management of thalassemia, 2nd Edition revised 2008; 2Angelucci E et al. Haematologica 2008;93:741–752
  78. 78. Primary goals of chelation therapy Complete chelation The primary goals of iron chelation therapy are to remove excess iron and provide protection from the effects of toxic iron Iron balance Removal of iron at a rate equal to transfused iron input Prevents end- organ damage due to iron Normalization of stored tissue iron May take years in established iron overload Safe levels of tissue iron differs between organs Control of toxic iron over 24-hr period 24-hr control of NTBI/LPI and intracellular labile iron Prevents end- organ damage due to iron
  79. 79. Goals of chelation Therapy is achieved by: • Keeping serum ferritin <1000-2,000 ng/mL or • LIC <15 mg/g dry weight
  80. 80. Iron chelating agents • Desferrioxamine (DFO) • Deferiprone • Deferasirox
  81. 81. Management: iron chelators Agent Route T1/2 hours Schedule Clearance Toxicity Deferoxamine IV/SQ Slow infusion 0.5 8-24 hours 5-7 days per week Renal and hepatic Infusion site reactions, allergic reactions, ocular and auditory Deferiprone Oral 2-3 3 daily Renal Nausea/ vomiting, arthropathy, neutropenia, agranulocytosis Desferrioxamine Oral 12-16 1 daily Hepatic Bad taste, nausea, epigastric pain, rash
  82. 82. Desferrioxamine Regular rotation of the site of infusion allows proper absorption of the medication and decreases the risk of skin breakdown and scar tissue formation. The most common sites are abdomen, thighs and upper arms.
  83. 83. Deferioxamine……contd Intensive chelation with Desferrioxamine – continuous 24-hourly infusions IV or SC. Indications: a) Persistently high serum ferritin; b) LIC > 15 mg/g dry weight; c) Significant heart disease, and; d) Prior to pregnancy or bone marrow transplantation Dose: 50 mg/kg/day (up to 60 mg/kg/day) In-dwelling catheters: danger of infection and thrombosis
  84. 84. Fetal Hb Induction
  85. 85. Induction of fetal hemoglobin Hb F enhancement • Hydroxyurea • Myelaran • Butyrate derivatives • Erythropoietin • 5-Azacytadine
  86. 86. • Increasing the synthesis of fetal hemoglobin can help to alleviate anaemia and thereby improve the clinical status of patients with thalassemia intermedia. • Agents including cytosine arabinoside and hydroxyurea may alter the pattern of erythropoiesis and increase the expression of alpha-chain genes.
  87. 87. • Erythropoietin has been shown to be effective, with a possible additive effect in combination with hydroxyurea. • Butyrate are a further experimental category, still unlicensed and with difficult intake.
  88. 88. SPLENECTOMY
  89. 89. Deferred as long as possible. At least till 5-6 yrs age. Indications: • Massive splenomegaly causing mechanical discomfort • Blood requirements >200-220 ml/kg/year • Hypersplenism
  90. 90. The risk of splenectomy Overwhelming infection Age—(<2 years of age) Time since splenectomy (1- 4 years after surgery) Immune status of patient Commonly associated pathogen Streptococcus pneumoniae Haemophilus influenzae Neisseria meningitidis
  91. 91. Preventative measures Immunoprophylaxis–  At least 2 weeks before splenectomy  Pneumococcus/meningococcus/Hemophilus Chemoprophylaxis-  Chemoprophylaxis with life-long oral penicillin. Education
  92. 92. Only curative option available. Overall outcome depends on- • Inadequate chelation therapy, • hepatomegaly, • presence of portal fibrosis. Treatment-related mortality is approximately 10%. Bone marrow/stem cell transplantation Guideline- Thalassemia International Federation-2008
  93. 93. Risk stratification for BMT  Hepatomegaly >3cms  Liver fibrosis  Inadequate chelation  Class I – no risk factors  Class II- one to two risk factors  Class III- all three risk factors
  94. 94. Outcome of BMT in thalassemia Guideline- Thalassemia International Federation-2008 Class probabilities of survival (%) disease-free survival (%) risk of rejection (%) risk of mortality (% I 93 91 2 8 II 87 83 3 15 III 79 58 28 19
  95. 95. B. Curative treatment in thalassemia • Stem cell transplantation • Gene therapy
  96. 96. Stem cell transplantation?
  97. 97. Stem cell transplantation
  98. 98. Whom to offer? Stem cell transplantation
  99. 99. Cost Vs Risk benefit of patient and Availability of DONOR Stem cell transplantation
  100. 100. Gene therapy
  101. 101. Gene therapy • Insertion of normal globin genes into marrow stem cell may ultimately cure Thalassemia . • Globin gene transfer in autologous CD34+cells is beginning to be evaluated • As per FDA recommendation, the current study is restricted to adults. Paediatric patients will be included at a later date after reviewing safety and efficacy data obtained in adults. Guidelines for the Management of transfusion dependent Thalassemia,3rd
  102. 102. Role of surgery in thalassemia • Cholelithiasis – Cholecystectomy • Choledocholithiasis – Choledocholithotomy • Cirrhosis (due to iron overload) – Liver biopsy and liver transplantation • Leg ulcer – Surgical dressing • Pathological fracture – Surgical correction • Spinal cord compression - Laminectomy
  103. 103. Follow up
  104. 104. Follow up Monthly: • Complete blood count • Complete blood chemistry (including liver function tests, BUN, creatinine) if taking deferasirox • Record transfusion volume.
  105. 105. Follow up Every 3 months: • Measurement of height and weight • Measurement of ferritin (trends in ferritin used to adjust chelation); • Complete blood chemistry, including liver function tests
  106. 106. Follow up Every 6 months: • Complete physical examination including Tanner staging, • Monitor growth and development • Dental examination
  107. 107. Follow up Every year: • Cardiac function – echocardiograph, ECG, Holter monitor (as indicated) • Endocrine function (TFTs, PTH, FSH/LH, fasting glucose, testosterone/estradiol, FSH, LH, IGF-1, Vitamin D levels) • Ophthalmological examination and auditory acuity • Viral serologies (HAV, HBV panel, HCV (or if HCV1, quantitative HCV RNA PCR), HIV) • Bone densitometry • Ongoing psychosocial support.
  108. 108. Follow up Every 2 years: • Evaluation of tissue iron burden • Liver iron measurement – R2 MRI, SQUID, or biopsy • T2* MRI measurement of cardiac iron (age .10 years).
  109. 109. C. Prevention and control  Career detection/Screening  Genetic counseling  Prenatal diagnosis  Health education
  110. 110. Screening • RBC indices (MCV, MCH, MCHC) • NESTROFT • HbA2
  111. 111. Career detection/screening Mass screening: NESTROFT (Necked Eye Single Tube Red Cell Osmotic Fragility Test) • Very cheap and easy to perform require small amount of blood • Based on principle that Thalassemic red cell resists hypotonic solution more than that of normal person • Give positive result on NESTROFT • Sensitivity 90-98% and specificity 85-90%
  112. 112. NESTROFT
  113. 113. Career detection/screening Automated CBC: • Thalassemic red cells are microcytic and hypochromic • WHO recommends MCV <77fl and MCH <27 pg as screening tools to pick up cases for confirmation by electrophoresis DCIP (Di Chloro phenol indol phenol): Screening for Hb E
  114. 114. Genetic counseling • Index case parents and relatives. • Antenatal visits of pregnant mothers.
  115. 115. Genetic counseling
  116. 116. • β/α ratio: <0.025 in fetal blood • Chorionic villous biopsy (10-12 weeks) • Cordocentesis • Amniocentesis (15-18th week) Analysis of fetal DNA • PCR to detect β globin gene Prenatal diagnosis
  117. 117. Chorionic Villus Biopsy
  118. 118. Health education/awareness • Knowledge of genetic nature of thalassemia • Transmission of the disease • Ways to avoid to have further child with the disease • Aware about economic burden to the family and govt.
  119. 119. Prognosis
  120. 120. Thalassemia major-life expectancy: • Without regular transfusion - Less than 10 years • With regular transfusion and no or poor iron chelation - Less than 25 years • With regular transfusion and good iron chelation - 40 years, or longer? The commonest cause of death is iron overload
  121. 121. Conclusion • Management needs extensive hands • Prevention program is rudimentary • Awareness about thalassemia is though increasing still very much lacking • Manpower is developing-good news • Thalassemia center dedicated to children to be established
  122. 122. Thalassemia day 8th May is the international Thalassemia Day. This day is dedicated to Thalassemia, to raise public awareness for prevention of Thalassemia and to highlight the importance of clinical care for Thalassemia patients in all countries.
  123. 123. Thank You

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